2.1. TRANSFORMING GROWTH FACTOR-BETA
The transforming growth factor (TGF) family of growth modulating peptides consists of two structurally and functionally dissimilar molecules, TGF-.alpha. and TGF-.beta.. Transforming growth factor-Beta (TGF-.beta.) is a member of a recently described family of polypeptides that regulate cellular differentiation and proliferation. Other members of this family include Mullerian inhibitory substance (Cate et al., 1986, Cell 45:685-698), the inhibins (Mason et al., 1985, Nature 318:659-663) and a protein predicted from a transcript of the decapentaplegic gene complex of Drosphila (Padgett et al., 1987, Nature 325:81-84).
Transforming growth factor-beta (TGF-.beta.) consists of two identical disulfide linked subunits having molecular weights of 13,000 (Assoian et al.,, 1983, J. Biol. Chem. 258:7155-7160; Frolik et al., 1983, Proc. Natl. Acad. Sci. USA 80:3676-3680; Frolik et al., 1984, J. Biol. Chem. 260:10995-11000). It has been purified from several tissue sources including placenta (Frolik et al., 1983, Nature 325:81-84), blood platelets (Childs et al., 1982, Proc. Natl. Acad. Sci. USA 79:5312-5316; Assoian et al., 1983, J. Biol. Chem. 258:7155-7160), kidney (Roberts et al., 1983, Biochemistry 22:5692-5698), and demineralized bone (Seyedin et al., 1985, Proc. Natl. Acad. Sci. USA 82:119-123). In the presence of 10% serum and epidermal growth factor, TGF-.beta. promotes the anchorage independent growth of normal rat kidney fibroblasts (Roberts et al., 1981, Proc. Natl. Acad. Sci. USA 78:5339-5343; Roberts et al., 1982, Nature 295:417-419; Twardzik et al., 1985, J. Cell. Biochem. 28:289-297); in the presence of 10% serum alone, it is able to induce colony formation of AKR-2B fibroblasts (Tucker et al., 1983, Cancer Res. 43:1518-1586). TGF-.beta. has also been shown to cause fetal rat muscle mesenchymal cells to differentiate and produce cartilage specific macromolecules (Seyedin et al., 1986, J. Biol. Chem. 261:5693-5695).
In contrast to its effect on cell proliferation, TGF-.beta. purified from human platelets as well as a functionally related protein isolated from African green monkey cells (BSC-1) has been shown to inhibit the growth of certain cells in culture (Tucker et al., 1984, Science 226:704-707). TGF-.beta. has also been shown to inhibit the growth of several human cancer cell lines (Roberts et al., 1985, Proc. Natl. Acad. Sci. USA 82:119-123). This bifunctional inhibitory/stimulatory effect of TGF-.beta. may depend on several factors including cell type and the physiological state of the cells (for review see Sporn et al., 1986, Science 233:532-534).
cDNA clones coding for human (Derynck et al., 1985, Nature 316:701-705), mouse (Derynck et al., 1986, J. Biol. Chem. 261:4377-4379), and simian (Sharples et al., 1987, DNA 6:239-244) TGF-.beta. have been isolated. DNA sequence analysis of these clones indicates that TGF-.beta. is synthesized as a large precursor polypeptide, the carboxy terminus of which is cleaved to yield the mature TGF-.beta. monomer. Strong sequence homology has been found throughout the TGF-.beta. precursor protein from all of the above sources.
Very recently a protein isolated from bovine demineralized bone has been identified as being related to TGF-.beta. (Seyedin et al., 1987, J. Biol. Chem. 262:1946-1949). The protein has also been isolated from porcine platelets (Cheifetz et al., 1987, Cell 48:409-415), a human prostatic adenocarcinoma cell line, PC-3 (Ikeda et al., 1987, Biochemistry 26:2406-2410), and a human glioblastoma cell line (Wrann et al., 1987, EMBO 6:1633-1636). Partial amino acid sequence of this protein indicated that it was homologous to TGF-.beta. and has been termed TGF-.beta.2. The human (Derynck et al., 1985, Nature 316:701-705), mouse (Derynck et al., 1986, J. Biol. Chem. 261:4377-4379) and simian (Sharples et al., 1987, DNA 6:239-244) TGF-.beta. described previously has been termed TGF-.beta.1.